Engineering anti-Lewis-Y hu3S193 antibodies with improved therapeutic ratio for radioimmunotherapy of epithelial cancers

Ingrid J.G. Burvenich, Fook-Thean Lee, Graeme J. O’Keefe, Dahna Makris, Diana X Cao, Sylvia Jie Gong, Angela Rigopoulos, Laura C. Allan, Martin W Brechbiel, Zhanqi Liu, Paul A. Ramsland, Andrew M. Scott

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Abstract

Background: The aim of the study was to explore Fc mutations of a humanised anti-Lewis-Y antibody (IgG1) hu3S193 as a strategy to improve therapeutic ratios for therapeutic payload delivery. Methods: Four hu3S193 variants (I253A, H310A, H435A and I253A/H310A) were generated via site-directed mutagenesis and radiolabelled with diagnostic isotopes iodine-125 or indium-111. Biodistribution studies in Lewis-Y-positive tumour-bearing mice were used to calculate the dose in tumours and organs for therapeutic isotopes (iodine-131, yttrium-90 and lutetium-177). Results: 111In-labelled I253A and H435A showed similar slow kinetics (t1/2β, 63.2 and 62.2 h, respectively) and a maximum tumour uptake of 33.11 ± 4.05 and 33.69 ± 3.77 percentage injected dose per gramme (%ID/g), respectively. 111In-labelled I253A/H310A cleared fastest (t1/2β, 9.1 h) with the lowest maximum tumour uptake (23.72 ± 0.85 %ID/g). The highest increase in tumour-to-blood area under the curve (AUC) ratio was observed with the metal-labelled mutants (90Y and 177Lu). 177Lu-CHX-A" DTPA-hu3S193 I253A/H310A (6:1) showed the highest tumour-to-blood AUC ratio compared to wild type (3:1) and other variants and doubling of calculated dose to tumour based on red marrow dose constraints. Conclusions: These results suggest that hu3S193 Fc can be engineered with improved therapeutic ratios for 90Y- and 177Lu-based therapy, with the best candidate being hu3S193 I253A/H310A for 177Lu-based therapy.

Original languageEnglish
Article number26
Number of pages13
JournalEJNMMI Research
Volume6
Issue number1
DOIs
Publication statusPublished - 1 Dec 2016

Keywords

  • Antibody engineering
  • Lewis-Y
  • Payload delivery
  • Small animal imaging
  • Therapeutic ratio

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